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ID PMID Title PublicationDate abstract
21569625 Lipoxins as biomarkers of lupus and other inflammatory conditions. 2011 May 15 Inflammatory events persist in systemic lupus erythematosus (lupus) despite the use of anti-inflammatory (both steroidal and non-steroidal) and immunosuppressive drugs leading to delay in the healing/repair process and so tissue/organ damage continues. The continuation of inflammation in lupus could be attributed to failure of the resolution process due to deficiency of potent endogenous pro-resolution-inducing molecules such as lipoxin A4 (LXA4). It is likely that progression and flares of lupus and lupus nephritis are due to decreased formation and release of LXA4. Hence, administration of LXA4 and its analogues could be of benefit in lupus. Furthermore, plasma and urinary measurement of lipoxins may be used to predict prognosis and response to therapy. It is likely that lipoxins and other bioactive anti-inflammatory lipids such as resolvins, protectins, maresins and nitrolipids play a significant role in other auto-immune diseases such as rheumatoid arthritis, type 1 diabetes mellitus and multiple sclerosis and hence, could be of significant benefit in these diseases.
21466494 Methotrexate: a drug of the future in ulcerative colitis? 2011 Sep Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is thought to affect 1780000 patients in USA and Europe. Its incidence is increasing rapidly in Asia. Drugs with proven clinical activity that are currently used in UC patients include salicylates, steroids, azathioprine and infliximab. None of them is active in every patient and all carry significant side effects. There is a need for other active drugs in UC. Low dose methotrexate has been used for decades in psoriasis, rheumatoid arthritis and Crohn's disease. In these diseases, it is an active, well tolerated and cheap drug. In UC there have been several open series, most of which are retrospective. Overall, these studies have shown promising results, with response rates of 50 to 72 %. There have been two randomized clinical trials of methotrexate vs placebo in UC. Both were negative but methotrexate was prescribed orally at suboptimal doses. So far, there is no evidence for the efficacy of methotrexate in UC. Therefore, there is a need for clinical trials with methotrexate using adequate dosage and the parenteral route. Two multicenter randomized trials of methotrexate 25 mg/week parenterally vs placebo are either ongoing (METEOR, the European trial) or being built up (MERIT, the US trial). These trials should determine if methotrexate is a valuable therapeutic option in UC.
21333642 Hepcidin: a novel peptide hormone regulating iron metabolism. 2011 May 12 BACKGROUND: Hepcidin is a low-molecular weight hepatic peptide regulating iron homeostasis. Hepcidin inhibits the cellular efflux of iron by binding to, and inducing the internalization and degradation of, ferroportin, the exclusive iron exporter in iron-transporting cells. It has been recently recognized as a main hormone behind anemia of chronic disease. METHOD: A comprehensive literature search was conducted from the websites of Pubmed Central, the US National Library of Medicine's digital archive of life sciences literature (http://www.pubmedcentral.nih.gov/) and the National Library of Medicine (http://www.ncbl.nlm.nih.gov). The data was also assessed from journals and books that published relevant articles in this field. RESULT: Hepcidin regulates iron uptake constantly on a daily basis, to maintain sufficient iron stores for erythropoiesis. Hepcidin, by its iron regulatory action on iron metabolism may be expected to have an important role in immune regulation, inflammatory diseases and malignancies. Hepcidin is the underlying cause of anemia in these clinical settings. CONCLUSION: Hepcidin analysis may prove to be a novel tool for differential diagnosis and monitoring of disorders of iron metabolism, and establishment of therapeutic measures in various disease conditions like hereditary hemochromatosis, anemia associated with chronic kidney disease, rheumatoid arthritis and cancers.
21261674 Cutaneous Hodgkin-type lymphoproliferative lesion associated with immunomodulatory therapy 2011 May Immunomodulatory drugs have demonstrated efficacy in the therapy against autoimmune diseases such as rheumatoid arthritis, Crohn's disease or ulcerative colitis. Tumor necrosis factor-α (TNF-α) represents a target molecule for the treatment of these entities. Use of monoclonal antibodies can block the proinflammatory function of TNF-α. It has been shown that this action can reactivate quiescent chronic diseases as well as modify the immune response or potentiate carcinogens, thereby increasing the risk of secondary tumor development. In this context, different types of solid or hematological tumors have been documented. We present the case of a male with chronic ulcerative colitis who secondarily developed a cutaneous Hodgkin-type lymphoproliferative lesion associated with immunodeficiency. This secondary tumor developed after 6 months of treatment with anti-TNF-α.
21221847 Hydroxychloroquine: from malaria to autoimmunity. 2012 Apr Quinine was first recognized as a potent antimalarial agent hundreds of years ago. Since then, the beneficial effects of quinine and its more advanced synthetic forms, chloroquine and hydroxychloroquine, have been increasingly recognized in a myriad of other diseases in addition to malaria. In recent years, antimalarials were shown to have various immunomodulatory effects, and currently have an established role in the management of rheumatic diseases, such as systemic lupus erythematosus and rheumatoid arthritis, skin diseases, and in the treatment of chronic Q fever. Lately, additional metabolic, cardiovascular, antithrombotic, and antineoplastic effects of antimalarials were shown. In this review, we discuss the known various immunomodulatory mechanisms of antimalarials and the current evidence for their beneficial effects in various diseases and in potential novel applications.
21136209 In vitro selection of a peptide inhibitor of human IL-6 using mRNA display. 2011 Jun Interleukin-6 (IL-6) plays a crucial role in malignant diseases, such as rheumatoid arthritis, Castleman disease, and multiple myeloma, and as such, is an attractive therapeutic target. Here, the authors isolated a novel IL-6 inhibitor peptide by in vitro selection using mRNA display. The authors first used a random-primed human cDNA library to isolate IL-6-binding peptides. After four rounds of selection, a 19-amino acid peptide named CA11 was selected and confirmed to specifically interact with IL-6. The authors then performed an alanine scan analysis of CA11 and determined the amino acid residues necessary to interact with IL-6. Next, the authors constructed a CA11-based partially randomized library and after ten more rounds of selection, isolated several groups of peptides. The most frequently occurring sequence, RA07, bound to IL-6 with 3 to 4-fold higher affinity than CA11. Furthermore, RA07 inhibited IL-6-dependent KT-3 cell proliferation in a dose-dependent manner. ELISAs revealed that RA07 could not inhibit IL-6 from binding to the IL-6 receptor (IL-6R), but could inhibit the IL-6/IL-6 complex binding to gp130.
23252525 Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. 2012 Dec 20 BACKGROUND: Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA. METHODS: We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension. RESULTS: At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range. CONCLUSIONS: Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).
23229350 Modulation of Th1 cytokines and inflammatory mediators by Euphorbia hirta in animal model 2013 Oct Euphorbia hirta L. (Euphorbiaceae) (E. hirta) is a tree locally used as a traditional medicine in Africa and Australia to treat numerous diseases such as hypertension, respiratory ailments, tumors, antipyretic, anti-inflammatory activities. In the present study, we investigated the anti-arthritic activity of fresh leaves of E. hirta ethanol extract that was found to inhibit the production of inflammatory mediators and cytokines of adjuvant arthritis in rats. Adjuvant arthritis was induced in rats (Wistar) by the subplantar injection of 0.05 ml freshly prepared suspension (5.0 mg/ml) of steam killed Mycobacterium tuberculli in liquid paraffin. Animals were treated with graded doses of 25, 50, 100 and 200 mg/kg of E. hirta ethanol extract, p.o. E. hirta significantly inhibited the swelling of the adjuvant-induced arthritis. Moreover, E. hirta at higher dose (200 mg/kg) showed 40.54 ± 1.09 % of CD3+, 15.1 ± 0.76 % of CD4+, 12.2 ± 1.18 % of CD8+ T cell receptor and 17.6 ± 1.11 % gated of CD19+ B cell receptor revealing a down regulation of adjuvant-induced arthritis as compared to the corresponding valves of the arthritic control rats. According to the results shown in Tables 1, 2, the production of IL-1β, TNF-α, IL-2 and IFN-γ were increased in splenocytes of arthritic rats and this increased level was reduced by E. hirta. Also, E. hirta significantly down regulated lipopolysaccharide (LPS)-induced production of nitric oxide production in peritoneal macrophages. These results suggest that E. hirta exhibits an improvement in adjuvant-induced arthritis through down regulation of activated macrophages and T lymphocytes functions. Such unique effects of E. hirta shown on adjuvant arthritis rat model may be advantageous to the long-term treatment of clinical rheumatoid arthritis. Table 1 Effect of E. hirta and prednisolone (Pred) on LPS-induced IL-1β and TNF-α productions from splenocytes in Mycobacterium tuberculli-induced inflammatory arthritic rats Treatment Dose (mg/kg) IL-1β (pg/ml) TNF-α (pg/ml) Arthritic control (AC) - 323.56 ± 31.65 180.91 ± 24.12 E. hirta 25 311.19 ± 29.08* 171.43 ± 22.54* E. hirta 50 287.12 ± 26.98* 164.54 ± 21.76** E. hirta 100 243.12 ± 19.21*** 157.30 ± 18.54*** E. hirta 200 215.21 ± 16.05*** 138.43 ± 17.98*** Prednisolone (Pred) 5 187.18 ± 15.21*** 123.77 ± 15.12*** Normal control (NC) - 54.12 ± 12.54 71.94 ± 12.12 Each value indicates the mean ± SEM of six animals AC arthritic control, NC normal control; E. hirta (25, 50, 100 and 200 mg/kg) and prednisolone (5 mg/kg) were given p.o. from day 0 to day 21 after Mycobacterium tuberculli injection, respectively * p < 0.05; ** p < 0.01; *** p < 0.001, compared to arthritic control Table 2 Effect of E. hirta and Prednisolone (Pred) on Con A-induced IL-2 and IFN-γ productions from splenocytes in Mycobacterium tuberculli-induced inflammatory arthritic rats Treatment Dose (mg/kg) IL-2 (pg/ml) IFN-γ (pg/ml) Arthritic control (AC) - 235.98 ± 15.23 165.95 ± 13.87 E. hirta 25 225.12 ± 14.76** 154.76 ± 11.07** E. hirta 50 207.76 ± 13.87** 134.76 ± 11.01** E. hirta 100 189.98 ± 12.65 *** 110.64 ± 10.98*** E. hirta 200 157.84 ± 14.32 *** 98.54 ± 10.76*** Prednisolone (Pred) 5 131.08 ± 13.31*** 87.65 ± 10.61*** Normal control (NC) - 78.12 ± 12.04 31.87 ± 10.12 Each value indicates the mean ± SEM of six animals AC arthritic control, NC normal control; E. hirta (25, 50, 100 and 200 mg/kg) and prednisolone (5 mg/kg) were given p.o. from day 0 to day 21 after Mycobacterium tuberculli injection, respectively * p < 0.05; ** p < 0.01; *** p < 0.001, compared to arthritic control.
21609657 Golimumab for the treatment of psoriatic arthritis. 2011 May This paper presents a summary of the evidence review group (ERG) report into the use of golimumab for the treatment of psoriatic arthritis (PsA). The main clinical effectiveness data were derived from a single phase III randomised controlled trial (RCT: GO-REVEAL) that compared golimumab with placebo for treating patients with active and progressive PsA who were symptomatic despite the use of previous disease-modifying antirheumatic drugs or non-steroidal anti-inflammatory drugs. The 14-week data showed that, compared with placebo, golimumab 50 mg significantly improved joint disease response as measured by American College of Rheumatology (ACR) 20 [relative risk (RR) 5.73, 95% confidence interval (CI) 3.24 to 10.56] and Psoriatic Arthritis Response Criteria (PsARC) (RR 3.45, 95% CI 2.49 to 4.87), and skin disease response as measured by the Psoriasis Area and Severity Index (PASI) 75 (RR 15.95, 95% CI 4.62 to 59.11). The 24-week absolute data showed that these treatment benefits were maintained. There was a significant improvement in patients' functional status as measured by the Health Assessment Questionnaire (HAQ) change from baseline at 24 weeks (-0.33, p < 0.001). The open-label extension data showed that these beneficial effects were also maintained at 52 and 104 weeks. However, PASI 50 and PASI 90 at 14 weeks, and all of the PASI outcomes at 24 weeks, were not performed on the basis of intention-to-treat analysis. Furthermore, analyses of the 24-week data were less robust, failing to adjust for treatment contamination due to patient crossover at week 16. The manufacturer conducted a mixed treatment comparison (MTC) analysis. The ERG considered the assumption of exchangeability between the trials for the purpose of the MTC analysis to be acceptable, and the statistical approach in the MTC analysis to be reliable. Regarding the safety evaluation of golimumab, the manufacturer failed to provide longer-term data or to consider adverse event data of golimumab from controlled studies in other conditions, such as rheumatoid arthritis and ankylosing spondylitis. Although the adverse effect profile of golimumab appears similar to other anti-tumour necrosis factor (TNF) agents, the longer-term safety profile of golimumab remains uncertain. The manufacturer's submission presented a decision model to compare etanercept, infliximab, golimumab and adalimumab versus palliative care for patients with PsA. In the base-case model, 73% of the cohort of patients were assumed to have significant psoriasis (> 3% of body surface area). Estimates of the effectiveness of anti-TNF agents in terms of PsARC, HAQ change and PASI change were obtained from an MTC analysis of RCT data. The manufacturer failed to calculate incremental cost-effectiveness ratios (ICERs) correctly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer's claim that golimumab is a cost-effective treatment option, the manufacturer's own model showed that golimumab is not cost-effective compared with other biologics when the ICERs are correctly calculated. None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion. However, a key area in determining the cost-effectiveness of anti-TNF agents is whether they should be treated as a class. If all anti-TNF agents are considered equally effective then etanercept, adalimumab and golimumab have very nearly equal costs and equal quality-adjusted life-years (QALYs), and all have an ICER of about £ 15,000 per QALY versus palliative care, whereas infliximab with a higher acquisition cost is dominated by the other biologics.
23050608 Juvenile idiopathic arthritis in two tertiary centres in the Western Cape, South Africa. 2012 Oct 10 BACKGROUND: Juvenile idiopathic arthritis (JIA) is a disease that shows wide variations between differing populations. Since the recent international consensus on classification criteria, JIA has been widely described in many countries and population groups. There has been almost no data that describes JIA in an African, specifically Sub-Saharan African, setting. Therefore, the aim of this study is to describe disease characteristics, disease course, and functional disability in two tertiary centres in the Western Cape, South Africa and compare the findings to other JIA populations. METHODS: Eighty-six children were recruited during random clinic visits to rheumatology clinics at Tygerberg and Groote Schuur Hospital between April 2010 and April 2011. Children were diagnosed using International League of Associations for Rheumatology (ILAR) 2001 classification criteria. Consent was obtained and medical records examined. The Childhood Health Assessment Questionnaires (CHAQ) and visual analogue scales (VAS) for pain and general well-being were completed and all children were examined by a researcher in conjunction with a paediatric rheumatologist. HIV status as well as tuberculosis disease and treatment were investigated. RESULTS: A total of 86 children were enrolled. Eight children were excluded (2 HIV arthropathy, 1 TB arthritis, 1 SLE, 4 with insufficient data), leaving a total of 78 patients. There was an equal female to male ratio-39 males and 39 females. There were 6 systemic JIA patients (7.69%), 17 persistent oligoarthritis (21.79%), 4 extended oligoarthritis (5.12%), 11 polyarthritis rheumatoid factor (RF) positive (14.10%), 21 polyarthritis RF negative (26.9%), 1 psoriatic arthritis (1.28%), and 18 enthesitis-related arthritis (23%). The median CHAQ for the group was 0.5 (IQR 0.1-1.25), the median VAS for pain was 18 mm (IQR 4-42) and median VAS for general well-being was 25 mm (IQR 3-49). Enthesitis-related arthritis and polyarthritis disease subtypes in this South African population may be more common than seen in JIA populations described in northern Europe, India, United Kingdom, and Turkey. CONCLUSION: This Western Cape South African JIA population appears to have a different profile of JIA than what has been described elsewhere. Enthesitis-related arthritis and polyarthritis disease subtypes appear to be more prevalent. There are also significant challenges in this setting such as later presentation to pediatric rheumatologists, different disease characteristics, and variable disease courses.
21492466 Physician assessment of disease activity in JIA subtypes. Analysis of data extracted from 2011 Apr 14 OBJECTIVE: Although electronic medical records (EMRs) have facilitated care for children with juvenile idiopathic arthritis (JIA), analyses of treatment outcomes have required paper based or manually re-entered data. We have started EMR discrete data entry for JIA patient visits, including joint examination and global assessment, by physician and patient. In this preliminary study, we extracted data from the EMR to Xenobaseâ„¢ (TransMed Systems, Inc., Cupertino, CA), an application permitting cohort analyses of the relationship between global assessment to joint examination and subtype. METHODS: During clinic visits, data were entered into discrete fields in ambulatory visit forms in the EMR (EpicCareâ„¢, Epic Systems, Verona, WI). Data were extracted using Clarity Reports, then de-identified and uploaded for analyses to Xenobaseâ„¢. Parameters included joint examination, ILAR diagnostic classification, physician global assessment, patient global assessment, and patient pain score. Data for a single visit for each of 160 patients over a 2 month period, beginning March, 2010, were analyzed. RESULTS: In systemic JIA patients, strong correlations for physician global assessment were found with pain score, joint count and patient assessment. In contrast, physician assessment for patients with persistent oligoarticular and rheumatoid factor negative patients showed strong correlation with joint counts, but only moderate correlation with pain scores and patient global assessment. Conversely, for enthesitis patients, physician assessment correlated strongly with pain scores, and moderately with joint count and patient global assessment. Rheumatoid factor positive patients, the smallest group studied, showed moderate correlation for all three measures. Patient global assessment for systemic patients showed strong correlations with pain scores and joint count, similar to data for physician assessment. For polyarticular and enthesitis patients, correlation of patient global assessment with pain scores was strong. Moderate correlations were found between patient global assessment and joint count in oligoarticular and polyarticular patients. CONCLUSION: Data extraction from the EMR is feasible and useful to evaluate JIA patients for indicators of treatment responsiveness. In this pilot study, we found correlates for physician global assessment of arthritis differed, according to disease subtype. Further data extraction and analyses will determine if these findings can be confirmed, and will assess other outcome measures, compare longitudinal responses to treatment, and export extracted data to multi-center databases.
22238244 Primary Sjögren's syndrome as a systemic disease: a study of participants enrolled in an 2012 Jun OBJECTIVE: To study the prevalence of extraglandular manifestations in primary Sjögren's syndrome (SS) among participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry. METHODS: A total of 1,927 participants in the SICCA registry were studied, including 886 participants who met the 2002 American-European Consensus Group (AECG) criteria for primary SS, 830 "intermediate" cases who had some objective findings of primary SS but did not meet AECG criteria, and 211 control individuals. We studied the prevalence of immunologic and hematologic laboratory abnormalities, specific rheumatologic examination findings, and physician-confirmed thyroid, liver, and kidney disease, as well as lymphoma among SICCA participants. RESULTS: Laboratory abnormalities, including hematologic abnormalities, hypergammaglobulinemia, and hypocomplementemia, frequently occurred among primary SS cases and were more common among the intermediate cases than among control participants. Cutaneous vasculitis and lymphadenopathy were also more common among primary SS cases. In contrast, the frequency of physician-confirmed diagnoses of thyroid, liver, and kidney disease and lymphoma was low and only primary biliary cirrhosis was associated with primary SS case status. Rheumatologic and neurologic symptoms were common among all SICCA participants, regardless of case status. CONCLUSION: Data from the international SICCA registry support the systemic nature of primary SS, manifested primarily in terms of specific immunologic and hematologic abnormalities. The occurrence of other systemic disorders among this cohort is relatively uncommon. Previously reported associations may be more specific to select patient subgroups, such as those referred for evaluation of certain neurologic, rheumatologic, or other systemic manifestations.
21567383 A secretagogue-small interfering RNA conjugate confers resistance to cytotoxicity in a cel 2011 Oct OBJECTIVE: Sjögren's syndrome (SS) is characterized by xerophthalmia and xerostomia resulting from loss of secretory function due to immune cell infiltration in lacrimal and salivary glands. Current therapeutic strategies for SS use secretagogues to induce secretion via muscarinic receptor stimulation. The purpose of this study was to create a secretagogue-small interfering RNA (siRNA) conjugate to deliver siRNA into cells via receptor-mediated endocytosis, thereby altering epithelial cell responses to external cues, such as proinflammatory or death signals, while simultaneously stimulating secretion. METHODS: Based on our expertise with type 3 muscarinic receptor (M3), we used carbachol, a ligand specific for muscarinic receptor, as the secretagogue. Carbachol was synthesized with an active choline group and was conjugated with an siRNA that targets caspase 3. A human salivary gland (HSG) cell line was used to test the efficacy of this secretagogue-siRNA conjugate. RESULTS: Lipofectamine transfection of the conjugate into HSG cells resulted in a 78% reduction in the expression of the caspase 3 gene, while external conjugate treatment of HSG cells resulted in intracellular calcium release and induction of endocytosis at levels similar to those of carbachol stimulation, indicating that the siRNA and carbachol portions of the conjugate retained their function after conjugation. HSG cells treated with conjugate (without Lipofectamine transfection) exhibited a 50% reduction in caspase 3 gene and protein expression, indicating that our conjugate was effective in delivering functional siRNA into cells via receptor-mediated endocytosis. Furthermore, tumor necrosis factor α-induced apoptosis was significantly reduced in conjugate-treated cells. CONCLUSION: Our secretagogue-siRNA conjugate prevented cytokine-induced apoptosis in salivary gland epithelial cells, which is critical to maintaining fluid secretion and potentially reversing the clinical hallmark of SS.
22693311 A folate receptor-α-specific ligand that targets cancer tissue and not sites of inflammat 2012 Jul Folic acid has been frequently exploited to target attached drugs to cells that overexpress a folate receptor (FR). Unfortunately, folic acid and folate-linked drugs bind equally well to both major isoforms of the FR-that is, FR-α, which is primarily expressed on malignant cells, and FR-β, which is upregulated on activated monocytes and macrophages. Because both major isoforms of FR can be expressed simultaneously in the same organism, folic acid cannot enable selective targeting of therapeutic and imaging agents to either tumor masses or sites of inflammation. In an effort to develop a targeting ligand that can selectively deliver attached imaging and therapeutic agents to tumor cells, we constructed a reduced and alkylated form of folic acid, N(5), N(10)-dimethyl tetrahydrofolate (DMTHF) that exhibits selectivity for FR-α. METHODS: DMTHF-(99m)Tc was injected into mice bearing FR-α-expressing tumor xenografts and imaged by γ-scintigraphy. The selectivity for FR-α over FR-β in vivo was examined by γ-scintigraphic images of animal models of various inflammatory diseases such as apolipoprotein E-deficient mice with atherosclerosis, DBA/1 LacJ mice with induced arthritis, C57BL/6J mice with muscle injury, and BALB/C mice with both FR-α tumor and ulcerative colitis, by administration of equal doses of DMTHF-(99m)Tc and EC20-(99m)Tc. The uptake of radiochelates in various organs was quantified by biodistribution studies. DMTHF-near-infrared dye conjugate and DMTHF-Oregon green dye conjugates were synthesized and evaluated for FR-α selectivity over FR-β in rat peritoneal macrophages and human peripheral blood monocytes, respectively, by flow cytometry. Fluorescence-guided imaging was also performed using folate and DMTHF dye conjugates. RESULTS: The new targeting ligand was found to bind malignant cells in mice with solid tumor xenografts but not peripheral blood monocytes or inflammatory macrophages in animal models of atherosclerosis, rheumatoid arthritis, muscle injury, or ulcerative colitis. Results from optical and radioimaging studies and biodistribution experiments confirm the differential specificity of this new ligand for malignant masses. CONCLUSION: The new targeting ligand DMTHF enables selective noninvasive imaging and therapy of tumor tissues in the presence of inflammation.
22484575 Acute inflammation with induction of anaphylatoxin C5a and terminal complement complex C5b 2012 Jul OBJECTIVE: The purpose of this case report was to investigate local immune mechanisms present during an acute inflammatory flare initiated by viscosupplementation with hylan G-F 20 in a patient with osteoarthritis (OA) and past meniscectomy. EXPERIMENTAL DESIGN: A patient with a history of bilateral OA and partial left knee meniscectomy, who had received three injections of hylan G-F 20, was diagnosed with an acute flare reaction in the left knee. Her chart was evaluated for clinical, radiological, and laboratory findings and for clinical follow-up. Histopathological synovial examination and real-time polymerase chain reaction (RT-PCR) for genes with major roles in local inflammation and enzyme-linked immunosorbent assays (ELISAs) for markers of complement activation and cytokines were performed. To study the impact of the inflammatory and immune features we compared the case patient with groups of three representative OA and three rheumatoid arthritis (RA) patients. RESULTS: The patient exhibited evidence of highly increased acute phase reactant C-reactive protein (CRP) in the blood. The pathological examination of the synovial membrane identified abundant fibrinous exudate with numerous particles of hyaluronan surrounded by a dense infiltrate of neutrophils and eosinophils. The synovium had moderate hypertrophy and sclerosis as well as an inflammatory infiltrate predominantly composed of T lymphocytes and macrophages with scattered perivascular eosinophils and neutrophils. Immunoperoxidase staining identified numerous deposits of C5b-9 in the fibrinous exudates and the synovial membrane of the patient. Similar findings were observed in the RA patients, whereas deposits were rare in OA synovial samples. In addition, both anaphylatoxin C5a and the terminal complement complex C5b-9 were present at high levels, comparable to those in RA patients. The levels of mRNA for interleukin-1 beta (IL-1β), IL-6, and the neutrophil marker myeloperoxidase (MPO) were markedly increased compared to those in the RA and OA patients. CONCLUSIONS: This present study is indicative of a pseudo-septic acute inflammatory reaction in response to local accumulation of hylan G-F 20 with the activation of complement and local invasion of pro-inflammatory cells.
20498204 Peptide-based ELISAs are not sensitive and specific enough to detect muscarinic receptor t 2011 Jan OBJECTIVES: The detection of autoantibodies to the muscarinic receptor type 3 (M3R) in the serum of patients with Sjögrens syndrome (SS) by ELISA is controversial. A study was undertaken to test whether modification of M3R peptides could enhance the antigenicity and increase the detection of specific antibodies using an ELISA. METHODS: A series of controlled ELISAs was performed with serum from 71 patients with SS and 37 healthy volunteers (HV) on linear, citrullinated and/or cyclised and multi-antigenic peptides (MAP) of the three extracellular M3R loops to detect specific binding. RESULTS: Significant differences (p<0.05) in optical density (OD) between serum from patients and HV were detected for a cyclised loop 1-derived peptide and the negative control peptide. Furthermore, there were no statistically significant differences between the frequency of positive patients (defined as OD >2SDs above the mean of the HV) and HV on any of the peptides tested. CONCLUSIONS: Binding of serum from patients with SS to M3R-derived peptides does not differ from binding to a control peptide in an ELISA and no significant binding to M3R-derived peptides was found in the serum from individual patients compared with HV. These data suggest that peptide-based ELISAs are not sufficiently sensitive and/or specific to detect anti-MR3 autoantibodies.
22840992 Central and peripheral neurological complications of primary Sjögren's syndrome. 2012 Sep Primary Sjögren's syndrome (pSS) is an autoimmune inflammatory disorder characterized by lymphocytic infiltration of exocrine glands, mainly the lacrimal and salivary glands leading to a chronic sicca syndrome. However, extraglandular organ systems may frequently be involved, including both central and peripheral nervous systems. Clinically significant neurologic manifestations affect approximately 20% of patients and may be the first manifestation of the disease in at least 25% of the cases. The spectrum of pSS-related neuropathies is wide including sensory neuropathies, neuronopathies, sensory-motor neuropathies, mononeuritis multiplex related to vasculitis… Central nervous system involvement is composed by multiple sclerosis-like manifestations including acute and chronic myelopathies and by more diffuse manifestations (cognitive dysfunction, subacute aseptic meningitis, encephalopathy, psychiatric symptoms, chorea, seizures…). The diagnosis and treatment of such pSS-related manifestations must be optimized in order to avoid severe disability.
22814518 Neutrophil activation and B-cell stimulation in the pathogenesis of Felty's syndrome. 2012 Felty's syndrome (FS) is a severe arthritic disorder that features chronic neutrophil activation and progresses to neutropenia and susceptibility to unabated infections. The life‑threatening manifestations of FS have focused the attention of clinical experimenters who have made persistent efforts to find new and effective therapies. This review highlights important milestones in the research on FS and draws attention to recent studies on the antigen specificity of antibodies present in patients' sera. Recent data have indicated that immunoglobulins G (IgGs) in patients with FS bind selectively and specifically to deiminated histones and neutrophil extracellular chromatin traps (NETs). Deimination is the conversion of certain arginine residues in proteins to citrullines by the enzyme peptidylarginine deiminase 4. Earlier observations had indicated that IgGs in FS patients avidly bind to citrullinated peptides. These observations suggest that NETosis, the type of cell death that is defined by the release of NETs, provides autoantigens that stimulate B cell responses in this patient group. This insight parallels recent observations in other autoimmune conditions and lends support to the paradigm that NETosis plays a leading role in the pathogenesis of antiself immune responses. 
22073983 Evaluation of gastrointestinal symptoms in different patient groups using the visual analo 2011 Nov 10 BACKGROUND: Irritable bowel syndrome (IBS) and gastrointestinal (GI) dysmotility disorders have a similar clinical picture, although dysmotility disorders require the attention of a specialist. Patients with primary Sjögren's syndrome (pSS) have also been described to suffer from IBS-like symptoms. No objective marker is available to distinguish between the patients. A visual analogue scale has been developed for IBS patients (VAS-IBS) to measure treatment response of GI symptoms and well-being in patients with IBS. The aim of the present study was to examine if VAS-IBS could be used to compare the degree of GI complaints in different patient populations, to get an objective marker to differentiate between the patients. METHODS: The VAS-IBS consists of 7 VAS scales, namely, abdominal pain, diarrhoea, constipation, bloating and flatulence, vomiting and nausea, psychological well-being and the intestinal symptoms' influence on daily life. Consecutive female patients suffering from IBS, dysmotility disorders and pSS were asked to complete the VAS-IBS questionnaire when visiting the out-patient clinics. In addition, a control population consisting of healthy female volunteers was included. RESULTS: Healthy volunteers had almost no GI symptoms, whereas all 3 patient groups expressed symptoms. There was no statistical significant difference between IBS and dysmotility in any of the scales besides vomiting and nausea (p = 0.044). Except for constipation, patients with pSS had less severe symptoms than the others. CONCLUSION: The VAS-IBS questionnaire could be used to assess the level of GI symptoms. However, VAS scores do not help the clinicians to differentiate between IBS and other dysmotility disturbances.
21918897 Mycoplasma pneumoniae infection associated with urticarial vasculitis mimicking adult-onse 2012 Dec Mycoplasma pneumoniae is well known to be a frequent cause of atypical pneumonia worldwide. However, it may also present with a wide variety of clinical features, including cutaneous symptoms, which are not widely recognised. Urticarial vasculitis occurring with M. pneumoniae has been described to occur in only one other case report. This amalgamation of non-specific clinical symptoms and signs can lead to a diagnostic dilemma. We describe a case of M. pneumoniae infection presenting with extrapulmonary manifestations and urticarial vasculitis, which was misdiagnosed as adult-onset Still's disease (AOSD). Had immunosuppressive therapy been commenced for AOSD in the presence of undiagnosed infection, this may have resulted in potentially serious consequences. This case highlights the need to remain vigilant about diagnosing M. pneumoniae as its serological diagnosis may take weeks and it has many extrapulmonary manifestations, which can masquerade as other conditions.